Patient Characteristics and Outcomes of Gastrointestinal Stromal Tumor Patients Undergoing Imatinib Plasma Level Testing

<p> <p>Although gastrointestinal stromal tumor (GIST) is effectively treated with imatinib, there are a number of clinical challenges in the optimal treatment of these patients. The plasma steady-state trough level of imatinib has been proposed to correlate with clinical outcome. Plasma imatinib level may be affected by a number of patient characteristics. Additionally, the ideal plasma trough concentration of imatinib is likely to vary based on the <em>KIT</em> genotype (genotype determines imatinib binding affinity) of the individual patient. Patients’ genotype or plasma imatinib level may influence the type and duration of response that is appreciable by clinical evaluation.</p> <p>The objectives of this study were to determine effects of genotype on the type of response appreciable by current imaging criteria, to determine the distribution of plasma imatinib levels in patients with GIST, to determine factors that correlate with plasma imatinib level, to determine the incremental effects of imatinib dose escalation; and to explore the median plasma levels and outcomes of patients with various <em>KIT</em> mutations.</p> <p>We therefore obtained <em>KIT</em> mutation information and analyzed CT response for size and density measurement of GISTs at baseline and within the first four moths of imatinib treatment. In 126 patients with metastatic/unresectable disease, the <em>KIT</em> genotype of patients’ tumor was significantly associated with unique response characteristics measurable by CT. Furthermore, hepatic and peritoneal metastases differed in their response characteristics. A subgroup of patients with <em>KIT</em> exon 9 mutation, who received higher doses of imatinib and experienced higher trough imatinib levels, experienced improved progression-free survival similar to that of <em>KIT </em>exon 11 patients.</p> <p>Therefore, we have found that imatinib plasma levels were higher in patients with elevated Aspartate amino transferase, were women, were older, or were being treated concomitantly with CYP450 substrate drugs. As expected, CYP450 inducers correlated with a lower plasma imatinib levels in GIST patients. Renal metabolism of imatinib accounts for <10%, so it was not included in the analysis but may affect covariates. Interestingly, there was a trend for low imatinib levels and inferior progression-free survival in patients who had undergone complete gastrectomy. Patients with <em>KIT</em> exon 9 mutation in our cohort received higher imatinib doses, experienced higher trough imatinib levels, and experienced a PFS similar to that of <em>KIT</em> exon 11 patients.</p> <p>In conclusion, imatinib plasma levels are influenced by a number of patient characteristics. The optimal imatinib plasma level for individual patients is not known but is an area of intense investigation. Our study confirms patients with <em>KIT </em>exon 9 mutations benefit from high-dose imatinib and higher trough imatinib levels.</p> </p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2011

Author dc:creator

• Nolden, Laura

Contributors dc:contributor

• Jonathan Trent, MD, PhD
• Haesun Choi, MD
• Russell Broaddus, MD, PhD

• Gastrointestinal stromal tumor
• GIST
• imatinib mesylate
• plasma level testing
• KIT
• KIT mutation
• Choi criteria
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/139

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1171